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Int J Mol Sci. 2016 May 5;17(5). pii: E678. doi: 10.3390/ijms17050678.

SARS Coronavirus Papain-Like Protease Inhibits the TLR7 Signaling Pathway through Removing Lys63-Linked Polyubiquitination of TRAF3 and TRAF6.

Author information

1
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan. violet7053@gmail.com.
2
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan. spirit1126@hotmail.com.
3
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan. alvajou@gmail.com.
4
Department of Biotechnology, College of Health Science, Asia University, Wufeng, Taichung 413, Taiwan. shhuang@asia.edu.tw.
5
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan. bonny6789@gmail.com.
6
Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung 404, Taiwan. lei.joseph@gmail.com.
7
Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung 404, Taiwan. yjlin.kath@gmail.com.
8
Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming University, Taipei 112, Taiwan. szkung@ym.edu.tw.
9
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan. cwlin@mail.cmu.edu.tw.
10
Department of Biotechnology, College of Health Science, Asia University, Wufeng, Taichung 413, Taiwan. cwlin@mail.cmu.edu.tw.

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLPro) reportedly inhibits the production of type I interferons (IFNs) and pro-inflammatory cytokines in Toll-like receptor 3 (TLR3) and retinoic acid-inducible gene 1 (RIG-I) pathways. The study investigated the inhibitory effect and its antagonistic mechanism of SARS-CoV PLPro on TLR7-mediated cytokine production. TLR7 agonist (imiquimod (IMQ)) concentration-dependently induced activation of ISRE-, NF-κB- and AP-1-luciferase reporters, as well as the production of IFN-α, IFN-β, TNF-α, IL-6 and IL-8 in human promonocyte cells. However, SARS-CoV PLPro significantly inhibited IMQ-induced cytokine production through suppressing the activation of transcription factors IRF-3, NF-κB and AP-1. Western blot analysis with anti-Lys48 and anti-Lys63 ubiquitin antibodies indicated the SARS-CoV PLPro removed Lys63-linked ubiquitin chains of TRAF3 and TRAF6, but not Lys48-linked ubiquitin chains in un-treated and treated cells. The decrease in the activated state of TRAF3 and TRAF6 correlated with the inactivation of TBK1 in response to IMQ by PLPro. The results revealed that the antagonism of SARS-CoV PLPro on TLR7-mediated innate immunity was associated with the negative regulation of TRAF3/6-TBK1-IRF3/NF-κB/AP1 signals.

KEYWORDS:

Lys63-linked polyubiquitin chains; SARS-CoV; TRAF3; TRAF6; Toll-like receptor 7; imiquimod

PMID:
27164085
PMCID:
PMC4881504
DOI:
10.3390/ijms17050678
[Indexed for MEDLINE]
Free PMC Article

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